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3.2 eric leroy


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3.2 eric leroy

  1. 1. Ebola : Research at the heart of the african tropical forest <ul><li>LEROY Eric </li></ul><ul><ul><li>PhD & DVM </li></ul></ul><ul><ul><li>Research Director, UMR MIVEGEC (IRD224 / CNRS5291 / Université Montpellier 1) </li></ul></ul><ul><ul><li>Head of viral Emergent Diseases Unit, CIRMF, Gabon </li></ul></ul>CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
  2. 2. <ul><li>2000 human deaths </li></ul><ul><li>> 10,000 deaths in gorillas and chimpanzees: decline of 80% </li></ul>Ebola virus: an emergent pathogen infecting humans and animals <ul><ul><li>Ebola virus: an emergent pathogen </li></ul></ul><ul><ul><li>Recent discovery (1976) </li></ul></ul><ul><ul><li>Unique form among virology world </li></ul></ul><ul><ul><li>~ highest lethal pathogens : </li></ul></ul><ul><ul><li>80 % mortality within days </li></ul></ul>Lancet 1997; J Infect Dis 1999; Science 2004 Lancet 2002; Clin Infect Dis 2006 J Infect Dis 2011; Trans Roy Soc 2011
  3. 3. The fundamentals of the pathogen Emergence 1 Step 1: from the natural host to human Step 2: from exposure to infection 2 Step 3: from human to human 3
  4. 4. Tracking Ebola: from field to lab <ul><ul><li>Outbreak Field investigations </li></ul></ul><ul><ul><li>In situ cohort studies: ~ 400 patients </li></ul></ul><ul><ul><li>Animal trapping </li></ul></ul><ul><ul><li>Molecular virology, immunological studies </li></ul></ul><ul><ul><li>BSL4 lab, unique in sub saharian Africa </li></ul></ul><ul><ul><li>WHO reference center for viral haemorrhagic fevers in Central Africa </li></ul></ul><ul><li>Field studies </li></ul><ul><li>Laboratory investigations </li></ul><ul><ul><li>Human </li></ul></ul><ul><ul><li>Animal </li></ul></ul>
  5. 5. outbreak direct contact <ul><ul><li>Fruit bat species as Ebola virus reservoir as well as for Marburg virus </li></ul></ul><ul><ul><li>Multi-emergence into great apes and/or humans with spill over events from bats </li></ul></ul><ul><ul><li>Massive outbreaks in wild great ape populations with dramatic population decline </li></ul></ul>Step 1 to Emergence: From bats to humans J Infect Dis 2004; Science 2004; Nature 2005 ; Emerg Infec Dis 2005 Vect born Zoo Dis 2009; J Infect Dis 2010
  6. 6. Tracking and following the Ebola virus history for the understanding of its Genomic evolution <ul><ul><li>Viral strains in animals </li></ul></ul>Step 2: From exposure to infection, virus evolution J Gen Virol 2003; Science 2004 Proc Natl Acad Sc USA 2008 J Infect Dis 2011 Before Our study <ul><ul><li>Recombinant viruses </li></ul></ul><ul><ul><li>Lineage B </li></ul></ul><ul><ul><li>Lineage A </li></ul></ul><ul><ul><li>Genetic characterization of 16 strains among 18 known zaire ebolavirus </li></ul></ul><ul><ul><li>Two lineages with ancient ancestor </li></ul></ul><ul><ul><li>Long lasting circulation in Africa </li></ul></ul><ul><ul><li>First evidence of recombination </li></ul></ul><ul><ul><li>Viral strains in great apes </li></ul></ul>
  7. 7. Host response: Deep defective immunity <ul><ul><li>Aberrant innate immunity : </li></ul></ul><ul><ul><li>&quot;cytokine storm&quot; & absence of IFN I responses </li></ul></ul>CD3+CD4+ CD3+CD8+ <ul><ul><li>Absence of adaptative immunity </li></ul></ul>0.7% 11.0% 51.9% 0.9% 72.6% T8 CD95+ T4 CD95+ Fas mechanism <ul><ul><li>Deep immunosuppression by apoptosis of T cells </li></ul></ul>CTL DCD SURV 12.3% 5.4% 22.4% 43.6% T4 T8 46.2% 24.1%
  8. 8. Pathogenesis: virus replication and superantigen activity ? Nat Med 1999; Clin Exp immunol 2001 PLoS Neg Trop Dis 2010 J Virol 2011  -actin V  2 V  5.1 V  12 V  1 1 V  7 V  6 V  17 V  16 V  13.2 V  19 Controls Fatal cases Days before death 9 8 7 4 3 2 1 0
  9. 9. Step 3 of Emergence: From humans to humans Routes of transmission From animals From body fluids At the hospital Traditional healer Strategy to control outbreaks: Prevention only Barriers nursing Individual protection
  10. 10. Human asymptomatic infection of Ebola virus EBOV RNA+ <ul><ul><li>EBOV RNA+ detection in PBMC for two weeks </li></ul></ul><ul><ul><li>EBOV -IgG and -IgM detection three weeks post infection </li></ul></ul><ul><ul><li>Identical viral strain as for survivors and deceased </li></ul></ul><ul><ul><li>Strong and early inflammatory responses </li></ul></ul><ul><ul><ul><li>Real pathogenicity of Ebola virus? </li></ul></ul></ul><ul><ul><ul><li>Natural protective immunity? </li></ul></ul></ul><ul><ul><ul><li>Exposure: fruits with saliva from infected fruit bats ? </li></ul></ul></ul>7 9 16 23 <ul><ul><li>High overall EBOV -IgG prevalence in Gabon </li></ul></ul><ul><ul><li>Association with forested areas </li></ul></ul><ul><ul><li>T cell memory responses </li></ul></ul>
  11. 11. <ul><li>Ebola </li></ul><ul><li>Origin of massive and rapid apoptosis </li></ul><ul><li>Vaccine and/or therapeutic development </li></ul><ul><li>Global surveillance of emergent diseases </li></ul><ul><li>General survey, tracking of emergent diseases risk </li></ul><ul><li>Search for animal reservoirs of viruses </li></ul><ul><li>International research networks and local plateforms </li></ul>Perspectives